A DVERSE D RUG R EACTION R EPORTING

5.17.1 The sponsor should expedite the reporting to all concerned investigator(s)/institutions(s), to the IRB(s)/IEC(s), where required, and to the regulatory authority(ies) of all adverse drug reactions (ADRs) that are both serious and unexpected.

5.17.2 Such expedited reports should comply with the applicable regulatory requirement(s) and with the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting.

5.17.3 The sponsor should submit to the regulatory authority(ies) all safety updates and periodic reports, as required by applicable regulatory requirement(s).

5.18 Monitoring 5.18.1 Purpose

The purposes of trial monitoring are to verify that:

a) The rights and well-being of human subjects are protected.

b) The reported trial data are accurate, complete, and verifiable from source documents.

c) The conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s).

5.18.2 Selection and Qualifications of Monitors

a) Monitors should be appointed by the sponsor.

b) Monitors should be appropriately trained, and should have the scientific and/or clinical knowledge needed to monitor the trial adequately. A monitorís qualifications should be documented.

c) Monitors should be thoroughly familiar with the investigational product(s), the protocol, written informed consent form and any other written information to be provided to subjects, the sponsorís SOPs, GCP, and the applicable regulatory requirement(s).

5.18.3 Extent and Nature of Monitoring

The sponsor should ensure that the trials are adequately monitored. The sponsor should determine the appropriate extent and nature of monitoring. The determination of the extent and nature of monitoring should be based on considerations such as the objective, purpose, design, complexity, blinding, size, and endpoints of the trial. In general there is a need for on-site monitoring, before, during, and after the trial; however in exceptional circumstances the sponsor may determine that central monitoring in conjunction with procedures such as investigatorsí training and meetings, and extensive written guidance can assure appropriate conduct of the trial in accordance with GCP. Statistically controlled sampling may be an acceptable method for selecting the data to be verified.

5.18.4 Monitor's Responsibilities

The monitor(s) in accordance with the sponsorís requirements should ensure that the trial is conducted and documented properly by carrying out the following activities when relevant and necessary to the trial and the trial site:

a) Acting as the main line of communication between the sponsor and the investigator.

b) Verifying that the investigator has adequate qualifications and resources (see 4.1, 4.2, 5.6) and remain adequate throughout the trial period, that facilities, including laboratories, equipment, and staff, are adequate to safely and properly conduct the trial and remain adequate throughout the trial period.

c) Verifying, for the investigational product(s):

i) That storage times and conditions are acceptable, and that supplies are sufficient throughout the trial.

ii) That the investigational product(s) are supplied only to subjects who are eligible to receive it and at the protocol specified dose(s).

iii) That subjects are provided with necessary instruction on properly using, handling, storing, and returning the investigational product(s).

iv) That the receipt, use, and return of the investigational product(s) at the trial sites are controlled and documented adequately.

v) That the disposition of unused investigational product(s) at the trial sites complies with applicable regulatory requirement(s) and is in accordance with the sponsor.

d) Verifying that the investigator follows the approved protocol and all approved amendment(s), if any.

e) Verifying that written informed consent was obtained before each subject's participation in the trial.

f) Ensuring that the investigator receives the current Investigator's Brochure, all documents, and all trial supplies needed to conduct the trial properly and to comply with the applicable regulatory requirement(s).

g) Ensuring that the investigator and the investigator's trial staff are adequately informed about the trial.

h) Verifying that the investigator and the investigator's trial staff are performing the specified trial functions, in accordance with the protocol and any other written agreement between the sponsor and the investigator/institution, and have not delegated these functions to unauthorized individuals.

i) Verifying that the investigator is enroling only eligible subjects.

j) Reporting the subject recruitment rate.

k) Verifying that source documents and other trial records are accurate, complete, kept up-to-date and maintained.

l) Verifying that the investigator provides all the required reports, notifications, applications, and submissions, and that these documents are accurate, complete, timely, legible, dated, and identify the trial.

m) Checking the accuracy and completeness of the CRF entries, source documents and other trial-related records against each other. The monitor specifically should verify that:

i) The data required by the protocol are reported accurately on the CRFs and are consistent with the source documents.

ii) Any dose and/or therapy modifications are well documented for each of the trial subjects.

iii) Adverse events, concomitant medications and intercurrent illnesses are reported in accordance with the protocol on the CRFs.

iv) Visits that the subjects fail to make, tests that are not conducted, and examinations that are not performed are clearly reported as such on the CRFs.

v) All withdrawals and dropouts of enrolled subjects from the trial are reported and explained on the CRFs.

n) Informing the investigator of any CRF entry error, omission, or illegibility. The monitor should ensure that appropriate corrections, additions, or deletions are made, dated, explained (if necessary), and initialled by the investigator or by a member of the investigator's trial staff who is authorized to initial CRF changes for the investigator. This authorization should be documented.

o) Determining whether all adverse events (AEs) are appropriately reported within the time periods required by GCP, the protocol, the IRB/IEC, the sponsor, and the applicable regulatory requirement(s).

p) Determining whether the investigator is maintaining the essential documents (see 8.

Essential Documents for the Conduct of a Clinical Trial).

q) Communicating deviations from the protocol, SOPs, GCP, and the applicable regulatory requirements to the investigator and taking appropriate action designed to prevent recurrence of the detected deviations.

5.18.5 Monitoring Procedures

The monitor(s) should follow the sponsorís established written SOPs as well as those procedures that are specified by the sponsor for monitoring a specific trial.

5.18.6 Monitoring Report

a) The monitor should submit a written report to the sponsor after each trial-site visit or trial-related communication.

b) Reports should include the date, site, name of the monitor, and name of the investigator or other individual(s) contacted.

c) Reports should include a summary of what the monitor reviewed and the monitor's statements concerning the significant findings/facts, deviations and deficiencies, conclusions, actions taken or to be taken and/or actions recommended to secure compliance.

d) The review and follow-up of the monitoring report with the sponsor should be documented by the sponsorís designated representative.

5.19 Audit

If or when sponsors perform audits, as part of implementing quality assurance, they should consider:

5.19.1 Purpose

The purpose of a sponsor's audit, which is independent of and separate from routine monitoring or quality control functions, should be to evaluate trial conduct and compliance with the protocol, SOPs, GCP, and the applicable regulatory requirements.

5.19.2 Selection and Qualification of Auditors

a) The sponsor should appoint individuals, who are independent of the clinical trials/systems, to conduct audits.

b) The sponsor should ensure that the auditors are qualified by training and experience to conduct audits properly. An auditorís qualifications should be documented.

5.19.3 Auditing Procedures

a) The sponsor should ensure that the auditing of clinical trials/systems is conducted in accordance with the sponsor's written procedures on what to audit, how to audit, the frequency of audits, and the form and content of audit reports.

b) The sponsor's audit plan and procedures for a trial audit should be guided by the importance of the trial to submissions to regulatory authorities, the number of subjects in the trial, the type and complexity of the trial, the level of risks to the trial subjects, and any identified problem(s).

c) The observations and findings of the auditor(s) should be documented.

d) To preserve the independence and value of the audit function, the regulatory authority(ies) should not routinely request the audit reports. Regulatory authority(ies) may seek access to an audit report on a case by case basis when evidence of serious GCP non-compliance exists, or in the course of legal proceedings.

e) When required by applicable law or regulation, the sponsor should provide an audit certificate.